The p63 C-terminus is essential for murine oocyte integrity
Open Access
- 15 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-14
- https://doi.org/10.1038/s41467-020-20669-0
Abstract
The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3’-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.This publication has 62 references indexed in Scilit:
- DNA Damage-Induced Primordial Follicle Oocyte Apoptosis and Loss of Fertility Require TAp63-Mediated Induction of Puma and NoxaMolecular Cell, 2012
- DNA Damage in Oocytes Induces a Switch of the Quality Control Factor TAp63α from Dimer to TetramerCell, 2011
- Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apesProceedings of the National Academy of Sciences of the United States of America, 2011
- The C-terminus of p63 contains multiple regulatory elements with different functionsCell Death & Disease, 2010
- TAp63 Prevents Premature Aging by Promoting Adult Stem Cell MaintenanceCell Stem Cell, 2009
- In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contributeCell Death & Differentiation, 2008
- ΔNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2Proceedings of the National Academy of Sciences of the United States of America, 2007
- Structural evolution of C-terminal domains in the p53 familyThe EMBO Journal, 2007
- The nuclear function of p53 is required for PUMA-mediated apoptosis induced by DNA damageProceedings of the National Academy of Sciences of the United States of America, 2007
- The E3 ubiquitin ligase Itch controls the protein stability of p63Proceedings of the National Academy of Sciences of the United States of America, 2006